US7153958B2 - Farnesyl transferase inhibiting benzoheterocyclic derivatives - Google Patents

Farnesyl transferase inhibiting benzoheterocyclic derivatives Download PDF

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US7153958B2
US7153958B2 US10/432,292 US43229203A US7153958B2 US 7153958 B2 US7153958 B2 US 7153958B2 US 43229203 A US43229203 A US 43229203A US 7153958 B2 US7153958 B2 US 7153958B2
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Patrick René Angibaud
Marc Gaston Venet
Virginie Sophie Poncelet
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Janssen Pharmaceutica NV
Janssen Cilag SA
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Definitions

  • the present invention is concerned with novel benzoheterocyclic derivatives, the preparation thereof, pharmaceutical compositions comprising said novel compounds and the use of these compounds as a medicine as well as methods of treatment by administering said compounds.
  • Oncogenes frequently encode protein components of signal transduction pathways which lead to stimulation of cell growth and mitogenesis. Oncogene expression in cultured cells leads to cellular transformation, characterized by the ability of cells to grow in soft agar and the growth of cells as dense foci lacking the contact inhibition exhibited by non-transformed cells. Mutation and/or overexpression of certain oncogenes is frequently associated with human cancer.
  • a particular group of oncogenes is known as ras which have been identified in mammals, birds, insects, mollusks, plants, fungi and yeasts.
  • the family of mammalian ras oncogenes consists of three major members (“isoforms”): H-ras, K-ras and N-ras oncogenes.
  • ras oncogenes code for highly related proteins generically known as p21 ras .
  • the mutant or oncogenic forms of p21 ras will provide a signal for the transformation and uncontrolled growth of malignant tumor cells.
  • the precursor of the p21 ras oncoprotein must undergo an enzymatically catalyzed farnesylation of the cysteine residue located in a carboxyl-terminal tetrapeptide. Therefore, inhibitors of the enzymes that catalyzes this modification, i.e. farnesyl transferase, will prevent the membrane attachment of p21 ras and block the aberrant growth of ras-transformed tumors.
  • farnesyl transferase inhibitors can be very useful as anticancer agents for tumors in which ras contributes to transformation.
  • WO 97/16443, WO 97/21701, WO 98/40383 and WO 98/49157 there are described 2-quinolone derivatives which exhibit farnesyl transferase inhibiting activity.
  • WO 00/39082 describes a class of novel 1,2-annelated quinoline compounds, bearing a nitrogen- or carbon-linked imidazole, which show farnesyl protein transferase and geranylgeranyl transferase inhibiting activity.
  • Other quinolone compounds having farnesyl transferase inhibiting activity are described in WO 00/12498, 00/12499, 00/47574 and 01/53289.
  • the present invention concerns compounds of formula (I):
  • halo is generic to fluoro, chloro, bromo and iodo;
  • C 1-4 alkyl defines straight and branched chain saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, e.g.
  • C 1-6 alkyl includes C 1-4 alkyl and the higher homologues thereof having 5 to 6 carbon atoms such as, for example, pentyl, 2-methyl-butyl, hexyl, 2-methylpentyl and the like;
  • C 1-6 alkanediyl defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl and the branched isomers thereof;
  • haloC 1-6 alkyl defines C 1-6 alkyl containing one or more halo substituents for example trifluoromethyl;
  • C 2-6 alkenyl defines straight and branched chain hydrocarbon radicals
  • S(O) refers to a sulfoxide and “S(O) 2 ” to a sulfone.
  • Aryl defines phenyl, naphthalenyl or phenyl substituted with one or more substituents each independently selected from halo, C 1-6 alkyl, C 1-6 alkyloxy or trifluoromethyl, cyano, hydroxycarbonyl.
  • the pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form.
  • the compounds of formula (I) which have basic properties can be converted in their pharmaceutically acceptable acid addition salts by treating said base form with an appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic (i.e.
  • butanedioic acid maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids.
  • acid addition salts also comprises the hydrates and the solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
  • stereochemically isomeric forms of compounds of formula (I), as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of formula (I) may possess.
  • chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound.
  • All stereochemically isomeric forms of the compounds of formula (I) both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention.
  • Examples of compounds of formula (a) include those wherein one or more of the following restrictions apply:
  • a group of interesting compounds consists of those compounds of formula (I) wherein one or more of the following restrictions apply:
  • a particular group of compounds consists of those compounds of formula (I) wherein Z is C 1-2 alkanediyl, r is 0 or 1, s is 1, t is 0, R 1 is halo, C 1-6 alkyl or forms a bivalent radical of formula (a-1), R 2 is halo, cyano or C 1-6 alkyl, R 3 is hydrogen or a radical of formula (b-1) or (b-3), R 10 is hydrogen or -Alk-OR 13 , R 11 is hydrogen and R 12 is hydrogen or C 1-6 alkylcarbonyl and R 13 is hydrogen; R 4 is a radical of formula (c-2) or (c-3), wherein R 16 is hydrogen, R 17 is C 1-6 alkyl, R 18 is C 1-6 alkyl, R 18a is hydrogen; R 6 is hydrogen, C 1-6 alkyl, —CH 2 —C 3-10 cycloalkyl, —C 1-6 alkylCO 2 R 24 (R 24 ⁇ H,Et), aminocarbonylC
  • More preferred compounds are those compounds of formula (I) wherein Z is C 1-2 alkanediyl, r is 0 or 1, s is 1, t is 0, R 1 is halo, preferably chloro and most preferably 3-chloro, R 2 is halo, preferably 4-chloro or 4-fluoro, or cyano, preferably 4-cyano, R 3 is hydrogen or a radical of formula (b-1) or (b-3), R 9 is hydrogen, R 10 is hydrogen, R 11 is hydrogen and R 12 is hydrogen, R 4 is a radical of formula (c-2) or (c-3), wherein R 16 is hydrogen, R 17 is C 1-6 alkyl, R 18 is C 1-6 alkyl, R 18a is hydrogen; R 6 is hydrogen, C 1-6 alkyl, —CH 2 —C 3-10 cycloalkyl or —C 1-6 alkylAr 2 ; R 7 is oxygen or sulphur; or R 6 and R 7 together form a trivalent radical of formula (x-2) or (x-4
  • Especially preferred compounds are those compounds of formula (I) wherein X is —S—, Z is —CH 2 —, r and s are 1, t is 0, R 1 is halo, preferably chloro, and most preferably 3-chloro, R 2 is halo, preferably chloro, and most preferably 4-chloro, or cyano, preferably 4-cyano, R 3 is a radical of formula (b-1) or (b-3), R 9 is hydrogen, R 10 and R 11 are hydrogen and R 12 is hydrogen, R 4 is a radical of formula (c-2) or (c-3), wherein R 16 is hydrogen, R 17 is C 1-6 alkyl preferably methyl, R 18 is C 1-6 alkyl preferably methyl, R 18a is hydrogen; R 6 is hydrogen, C 1-6 alkyl, —CH 2 —C 3-10 cycloalkyl or -alkylAr 2 ; R 7 is oxygen or sulphur; or R 6 and R 7 together form a trivalent radical of formula (x-4
  • the most preferred compounds according to the invention are: 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-1-methyl-4,1-benzoxazepin-2(3H)-one, 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-1-methyl-4,1-benzothiazepin-2(3H)-one, 5-(3chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzoxazepine-2(3H)-thione, 7-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-y
  • the compounds of formula (I) and their pharmaceutically acceptable salts and N-oxides and stereochemically isomeric forms thereof may be prepared in conventional manner, for example by a process which comprises:
  • W 1 is a replaceable group, with an imidazole reagent serving to replace the group W 1 with an R 4 group of formula (c-1); or
  • this can be effected for example by N-alkylating an intermediate of formula (III), wherein W 1 is an appropriate leaving group such as, for example, chloro, bromo, methanesulfonyloxy or benzenesulfonyloxy, with an intermediate of formula (X) to form a compound of formula (I) in which R 4 is a group of formula (c-1) represented by compounds of formula (I-a):
  • the reaction can be performed in a reaction-inert solvent such as, for example, acetonitrile, and optionally in the presence of a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine. Stirring may enhance the rate of the reaction.
  • a reaction-inert solvent such as, for example, acetonitrile
  • a suitable base such as, for example, sodium carbonate, potassium carbonate or triethylamine. Stirring may enhance the rate of the reaction.
  • the reaction may conveniently be carried out at a temperature ranging between room temperature and reflux temperature.
  • compounds of formula (I-a) can be prepared by reacting an intermediate of formula (IIIa) in which W 1 is hydroxy with an intermediate of formula (X), wherein Y is oxygen or sulfur, such as, for example, a 1,1′-carbonyldiimidazole.
  • reaction may conveniently be conducted in a reaction-inert solvent, such as, e.g. tetrahydrofuran, optionally in the presence of a base, such as sodium hydride, and at a temperature ranging between room temperature and the reflux temperature of the reaction mixture.
  • a reaction-inert solvent such as, e.g. tetrahydrofuran
  • a base such as sodium hydride
  • the compounds of formula (I) wherein R 4 represents a radical of formula (c-2), R 3 is hydroxy and R 17 is C 1-6 alkyl, said compounds being referred to as compounds of formula (I-b-1) may be prepared by reacting an intermediate ketone of formula (IV) with an intermediate of formula (XIIa). Said reaction requires the presence of a suitable strong base, such as, for example, butyl lithium in an appropriate solvent, such as, for example, tetrahydrofuran, and the presence of an appropriate silane derivative, such as, for example, triethylchlorosilane. During the work-up procedure an intermediate silane derivative is hydrolyzed. Other procedures with protective groups analogous to silane derivatives can also be applied.
  • a suitable strong base such as, for example, butyl lithium in an appropriate solvent, such as, for example, tetrahydrofuran
  • silane derivative such as, for example, triethylchlorosilane.
  • the compounds of formula (I), wherein R 4 is a radical of formula (c-2), R 3 is hydroxy and R 17 is hydrogen, said compounds being referred to as compounds of formula (I-b-2) may be prepared by reacting an intermediate ketone of formula (IV) with a intermediate of formula (XIIb), wherein PG is a protective group such as, for example, a sulfonyl group, e.g. a dimethylamino sulfonyl group, which can be removed after the addition reaction. Said reaction is conducted analogously as for the preparation of compounds of formula (I-b-1), followed by removal of the protecting group PG, yielding compounds of formula (I-b-2).
  • the compounds of formula (I) wherein R 4 represents a radical of formula (c-3) may be prepared by reacting the compound of formula (IV) with the triazole reagent, preferably in a reaction-inert solvent such as tetrahydrofuran, in the presence of a strong base such as butyl lithium at a temperature ranging from ⁇ 78° C. to room temperature.
  • a strong base such as butyl lithium at a temperature ranging from ⁇ 78° C. to room temperature.
  • a strong base such as butyl lithium
  • the 3-mercapto derivative is methylated, this is conveniently effected with methyl iodide in the presence of a base such as sodium methylate.
  • Removal of the 3-mercapto group is conveniently effected with sodium nitrite, for example in THF/H 2 O in the presence of nitric acid.
  • the compounds of formula (1) wherein R 4 represents a radical of formula (c-4) may be prepared by reacting the compound of formula (IV) with the 3-bromopyridyl reagent, preferably in a reaction-inert solvent such as tetrahydrofuran, in the presence of a strong base such as butyl lithium at a temperature ranging from ⁇ 78° C. to room temperature.
  • the compounds of formula (I) may also be converted into each other via art-known reactions or functional group transformations.
  • a number of such transformations are already described hereinabove.
  • Other examples are hydrolysis of carboxylic esters to the corresponding carboxylic acid or alcohol; hydrolysis of amides to the corresponding carboxylic acids or amines; hydrolysis of nitrites to the corresponding amides; amino groups on imidazole or phenyl may be replaced by a hydrogen by art-known diazotation reactions and subsequent replacement of the diazo-group by hydrogen; alcohols may be converted into esters and ethers; primary amines may be converted into secondary or tertiary amines; double bonds may be hydrogenated to the corresponding single bond.
  • the intermediates and starting materials used in the above-described processes may be prepared in conventional manner using procedures known in the art for example as described in the above-mentioned patent specifications WO 97/16443, WO 97/21701, WO 98/40383, WO 98/49157 and WO 00/39082.
  • the starting materials used in processes b) and c) may be prepared by cyclisation procedures on appropriate starting materials, for example generally in accordance with the cyclisation procedures described above for process a) before the introduction of the imidazole moiety.
  • process c) it may be convenient to cyclise a compound of formula (XIII):
  • the compounds of formula (I) and some of the intermediates have at least one stereogenic center in their structure.
  • This stereogenic center may be present in a R or a S configuration.
  • the compounds of formula (I) as prepared in the hereinabove described processes are generally racemic mixtures of enantiomers which can be separated from one another following art-known resolution procedures.
  • the racemic compounds of formula (I) may be converted into the corresponding diastereomeric salt forms by reaction with a suitable chiral acid. Said diastereomeric salt forms are subsequently separated, for example, by selective or fractional crystallization and the enantiomers are liberated therefrom by alkali.
  • An alternative manner of separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the compounds of formula (I), the pharmaceutically acceptable acid addition salts and stereoisomeric forms thereof have valuable pharmacological properties in that they have a potent farnesyl protein transferase (FPTase) inhibitory effect.
  • FPTase farnesyl protein transferase
  • This invention provides a method for inhibiting the abnormal growth of cells, including transformed cells, by administering an effective amount of a compound of the invention.
  • Abnormal growth of cells refers to cell growth independent of normal regulatory mechanisms (e.g. loss of contact inhibition). This includes the abnormal growth of: (1) tumor cells (tumors) expressing an activated ras oncogene; (2) tumor cells in which the ras protein is activated as a result of oncogenic mutation of another gene; (3) benign and malignant cells of other proliferative diseases in which aberrant ras activation occurs.
  • tumor cells tumor cells expressing an activated ras oncogene
  • tumor cells in which the ras protein is activated as a result of oncogenic mutation of another gene
  • benign and malignant cells of other proliferative diseases in which aberrant ras activation occurs.
  • ras oncogenes not only contribute to the growth of tumors in vivo by a direct effect on tumor cell growth but also indirectly, i.
  • This invention also provides a method for inhibiting tumor growth by administering an effective amount of a compound of the present invention, to a subject, e.g. a mammal (and more particularly a human) in need of such treatment.
  • this invention provides a method for inhibiting the growth of tumors expressing an activated ras oncogene by the administration of an effective amount of the compounds of the present invention.
  • tumors which may be inhibited, but are not limited to, lung cancer (e.g. adenocarcinoma and including non-small cell lung cancer), pancreatic cancers (e.g. pancreatic carcinoma such as, for example exocrine pancreatic carcinoma), colon cancers (e.g.
  • colorectal carcinomas such as, for example, colon adenocarcinoma and colon adenoma
  • prostate cancer including the advanced disease, hematopoietic tumors of lymphoid lineage (e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma), myeloid leukemias (for example, acute myelogenous leukemia (AML)), thyroid follicular cancer, myelodysplastic syndrome (MDS), tumors of mesenchymal origin (e.g.
  • lymphoid lineage e.g. acute lymphocytic leukemia, B-cell lymphoma, Burkitt's lymphoma
  • myeloid leukemias for example, acute myelogenous leukemia (AML)
  • AML acute myelogenous leukemia
  • MDS myelodysplastic syndrome
  • mesenchymal origin e.g.
  • fibrosarcomas and rhabdomyosarcomas melanomas, teratocarcinomas, neuroblastomas, gliomas, benign tumor of the skin (e.g. keratoacanthomas), breast carcinoma (e.g. advanced breast cancer), kidney carcinoma, ovary carcinoma, bladder carcinoma and epidermal carcinoma.
  • This invention may also provide a method for inhibiting proliferative diseases, both benign and malignant, wherein ras proteins are aberrantly activated as a result of oncogenic mutation in genes. With said inhibition being accomplished by the administration of an effective amount of the compounds described herein, to a subject in need of such a treatment.
  • the benign proliferative disorder neuro-fibromatosis, or tumors in which ras is activated due to mutation or overexpression of tyrosine kinase oncogenes may be inhibited by the compounds of this invention.
  • the compound according to the invention can be used for other therapeutic purposes, for example:
  • the compounds of present invention are particularly useful for the treatment of proliferative diseases, both benign and malignant, wherein the K-ras B isoform is activated as a result of oncogenic mutation.
  • the present invention discloses the compounds of formula (I) for use as a medicine as well as the use of these compounds of formula (I) for the manufacture of a medicament for treating one or more of the above mentioned conditions.
  • the compound of the invention may be advantageously employed in combination with one or more other medicinal agents such as anti-cancer agents for example selected from platinum coordination compounds for example cisplatin or carboplatin, taxane compounds for example paclitaxel or docetaxel, camptothecin compounds for example irinotecan or topotecan, anti-tumor vinca alkaloids for example vinblastine, vincristine or vinorelbine, anti-tumor nucleoside derivatives for example 5-fluorouracil, gemcitabine or capecitabine, nitrogen mustard or nitrosourea alkylating agents for example cyclophosphamide, chlorambucil, carmustine or lomustine, anti-tumor anthracycline derivatives for example daunorubicin, doxorubicin or idarubicin; HER2 antibodies for example trastzumab; and antitumor podophyllotoxin derivatives for example etoposide
  • anti-cancer agents
  • the compounds according to the present invention can administered to a patient as described above in conjunction with irradiation; such treatment is may be especially beneficial as farnesyl transferase inhibitors can act as radiosensitisers for example as described in International Patent Specification WO 00/01411, enhancing the therapeutic effect of such irradiation.
  • Irradiation means ionizing radiation and in particular gamma radiation, especially that emitted by linear accelerators or by radionuclides that are in common use today.
  • the irradiation of the tumor by radionuclides can be external or internal.
  • the administration of the farnesyl transferase inhibitor commences up to one month, in particular up to 10 days or a week, before the irradiation of the tumor. Additionally, it is advantageous to fractionate the irradiation of the tumor and maintain the administration of the farnesyl transferase inhibitor in the interval between the first and the last irradiation session.
  • the amount of farnesyl protein transferase inhibitor, the dose of irradiation and the intermittence of the irradiation doses will depend on a series of parameters such as the type of tumor, its location, the patients' reaction to chemo- or radiotherapy and ultimately is for the physician and radiologists to determine in each individual case.
  • the present invention also concerns a method of cancer therapy for a host harboring a tumor comprising the steps of
  • the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
  • compositions of this invention an effective amount of a particular compound, in base or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, to aid solubility for example, may be included.
  • injectable solutions for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin.
  • Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions.
  • These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
  • Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
  • an effective amount would be from 0.01 mg/kg to 100 mg/kg body weight, and in particular from 0.05 mg/kg to 10 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing 0.5 to 500 mg, and in particular 1 mg to 200 mg of active ingredient per unit dosage form.
  • THF tetrahydrofuran
  • DIPE diisopropyl ether
  • DME 1,2-dimethoxyethane
  • EtOAc ethyl acetate
  • DCM dichloromethane
  • BuLi n-butyl lithium
  • Tetraphosphorus decasulfide (0.0305 mol) was added to a solution of intermediate (11) (0.0254 mol) in THF (300 ml). The mixture was stirred at 40° C. for 1 hour and then cooled. DCM was added. The precipitate was filtered off. The filtrate was washed with water, dried (MgSO 4 ), filtered and the solvent was evaporated till dryness. The residue (16 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /EtOAc 99.5/0.5; 20–45 ⁇ m). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from 2-propanone and DIPE.
  • Tetraphosphorus decasulfide (0.0075 mol) was added to a solution of intermediate (20) (0.0063 mol) in THF (50 ml). The mixture was stirred at 40° C. for 1 hour and then brought to room temperature. DCM was added. The precipitate was filtered off. The filtrate was washed with water, dried (MgSO 4 ), filtered and the solvent was evaporated till dryness. The residue (5 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 100%; 15–40 ⁇ m). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from acetonitrile and DIPE.
  • 3-mercapto-propanoic acid (0.00433 mol) was added slowly to a mixture of intermediate (17) (0.00456 mol) in dioxane (20 ml) and D (20 ml). The mixture was stirred at 80° C. for 5 hours. The solvent was evaporated till dryness. The product was used without further purification, yielding 3-[[[2-amino-5-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methyl]thio]-propanoic acid (intermediate 22).
  • BuLi 1.6M (10.2 ml) was added dropwise at ⁇ 70° C. under N 2 flow to a mixture of 1-methyl-1H-imidazole (0.0164 mol) in THF (25 ml). The mixture was stirred at ⁇ 70° C. for 30 min. ClSiEt 3 (0.0164 mol) was added. The mixture was brought slowly to 10° C. and cooled again to ⁇ 70° C. BuLi 1.6M (10.2 ml) was added dropwise. The mixture was stirred at ⁇ 70° C. for 1 hour, brought to ⁇ 30° C. and cooled again to ⁇ 70° C. A mixture of intermediate (12) (0.00747 mol) in THF (35 ml) was added dropwise.
  • the residue (4 g) was purified by column chromatography over silica gel (eluent: CH 2 Cl 2 /CH 3 OH/NH 4 OH 97.5/2.5/0.1 and 96/4/0.1; 15–40 ⁇ m). The pure fractions were collected and the solvent was evaporated. The residue was crystallized from acetonitrile and diethyl ether.
  • BuLi 1.6M (31.9 ml) was added dropwise at ⁇ 70° C. under N 2 flow to a mixture of 1-methyl-1H-imidazole (0.051 mol) in THF (85 ml). The mixture was stirred at ⁇ 70° C. for 30 min. ClSiEt 3 (0.051 mol) was added. The mixture was brought slowly to 10° C. and cooled again to ⁇ 70° C. BuLi 1.6M (31.9 ml) was added dropwise. The mixture was stirred at ⁇ 70° C. for 1 hour, brought to ⁇ 20° C., cooled again to ⁇ 70° C. and added dropwise at ⁇ 70° C.
  • Tetraphosphorus decasulfide (0.0097 mol) was added at room temperature to a solution of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (see Example B13) (0.0081 mol) in THF (50 ml). The mixture was stirred at room temperature for 2 hours and poured out into ice water. The precipitate was filtered off and taken up in K 2 CO 3 10%. The mixture was extracted with DCM and a small amount of methanol.
  • nBuLi (0.009 mol) was added dropwise at ⁇ 70° C. to a mixture of 3-bromo-pyridine (0.009 mol) in diethyl ether (10 ml) under N 2 flow. The mixture was stirred at ⁇ 70° C. for 15 minutes. A suspension of intermediate (31) (0.003 mol) in THF (30 ml) was added dropwise at ⁇ 70° C. The mixture was stirred at ⁇ 70° C. for 1 hour, then brought slowly to room temperature, stirred overnight and poured out into ice water. EtOAc was added. The mixture was extracted with EtOAc. The organic layer was separated, dried (MgSO 4 ), filtered, and the solvent was evaporated.
  • 2,2,2-trichloroethyl ester carbonochloridic acid (0.0008 mol) was added at room temperature to a mixture of 7-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-5-(3-chlorophenyl)-1,5-dihydro-1-methyl-4,1-benzothiazepin-2(3H)-one (0.0001 mol), obtained in example B11b, in DMF (2 ml).
  • the mixture was stirred at room temperature for 3 days and poured out into ice water. The precipitate was filtered off and dried, yielding 0.02 g.
  • the aqueous layer was extracted with EtOAc.
  • the ras-transformed cell phenotype reversion assay was performed essentially as described in WO 98/40383, pages 34–36.
  • the farnesyl protein transferase inhibitor secondary tumor model was used as described in WO 98/40383, page 37.

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8232402B2 (en) 2008-03-12 2012-07-31 Link Medicine Corporation Quinolinone farnesyl transferase inhibitors for the treatment of synucleinopathies and other indications
US8343996B2 (en) 2008-11-13 2013-01-01 Astrazeneca Ab Azaquinolinone derivatives and uses thereof

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* Cited by examiner, † Cited by third party
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EP2295549B1 (en) 2004-04-29 2015-02-25 U.S. Smokeless Tobacco Company LLC Nicotiana nucleic acid molecules and uses thereof
CN113072509B (zh) * 2021-03-01 2022-11-25 中国科学院成都有机化学有限公司 一种合成7-氨基氯硝西泮化合物的方法

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3682892A (en) 1970-12-23 1972-08-08 Hoffmann La Roche 7-hydroxy lower alkyl benzodiazepines
GB1435981A (en) 1972-07-13 1976-05-19 Hoffmann La Roche Benzodiazepine derivatives
US5116971A (en) 1986-04-01 1992-05-26 Boehringer Ingelheim Kg Substituted-1,4-diazepines
EP0317564B1 (en) 1986-07-31 1993-05-19 HUNT, Anthony Owen Flexible coupling
WO1996020184A1 (en) 1994-12-23 1996-07-04 Pfizer Inc. Naphthyl-benzoxazepines or -benzothiazepines as squalene synthetase inhibitors
WO1997016443A1 (en) 1995-10-31 1997-05-09 Janssen Pharmaceutica N.V. Farnesyl transferase inhibiting 2-quinolone derivatives
WO1997021701A1 (en) 1995-12-08 1997-06-19 Janssen Pharmaceutica N.V. Farnesyl protein transferase inhibiting (imidazol-5-yl)methyl-2-quinolinone derivatives
WO1998040383A1 (en) 1997-03-10 1998-09-17 Janssen Pharmaceutica N.V. Farnesyl transferase inhibiting 1,8-annelated quinolinone derivatives substituted with n- or c-linked imidazoles
WO1998049157A1 (en) 1997-04-25 1998-11-05 Janssen Pharmaceutica N.V. Farnesyltransferase inhibiting quinazolinones
WO1998055124A1 (en) 1997-06-02 1998-12-10 Janssen Pharmaceutica N.V. (imidazol-5-yl)methyl-2-quinolinone derivatives as inhibitors of smooth muscle cell proliferation
WO2000001386A1 (en) 1998-07-06 2000-01-13 Janssen Pharmaceutica N.V. Farnesyl protein transferase inhibitors for treating arthropathies
WO2000001411A1 (en) 1998-07-06 2000-01-13 Janssen Pharmaceutica N.V. Farnesyl protein transferase inhibitors with in vivo radiosensitizing properties
WO2000012499A1 (en) 1998-08-27 2000-03-09 Pfizer Products Inc. Alkynyl-substituted quinolin-2-one derivatives useful as anticancer agents
WO2000012498A1 (en) 1998-08-27 2000-03-09 Pfizer Products Inc. Quinolin-2-one derivatives useful as anticancer agents
WO2000039082A2 (en) 1998-12-23 2000-07-06 Janssen Pharmaceutica N.V. 1,2-annelated quinoline derivatives
WO2000047574A1 (en) 1999-02-11 2000-08-17 Pfizer Products Inc. Heteroaryl-substituted quinolin-2-one derivatives useful as anticancer agents
WO2001053289A1 (en) 2000-01-21 2001-07-26 Pfizer Products Inc. Anticancer compound and enantiomer separation method useful for synthesizing said compound

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2002864C (en) * 1988-11-29 1999-11-16 Eddy J. E. Freyne (1h-azol-1-ylmethyl) substituted quinoline, quinazoline or quinoxaline derivatives
TW316902B (ja) * 1994-12-28 1997-10-01 Janssen Pharmaceutica Nv
US6011029A (en) * 1996-02-26 2000-01-04 Bristol-Myers Squibb Company Inhibitors of farnesyl protein transferase

Patent Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3682892A (en) 1970-12-23 1972-08-08 Hoffmann La Roche 7-hydroxy lower alkyl benzodiazepines
GB1435981A (en) 1972-07-13 1976-05-19 Hoffmann La Roche Benzodiazepine derivatives
US5116971A (en) 1986-04-01 1992-05-26 Boehringer Ingelheim Kg Substituted-1,4-diazepines
EP0317564B1 (en) 1986-07-31 1993-05-19 HUNT, Anthony Owen Flexible coupling
WO1996020184A1 (en) 1994-12-23 1996-07-04 Pfizer Inc. Naphthyl-benzoxazepines or -benzothiazepines as squalene synthetase inhibitors
WO1997016443A1 (en) 1995-10-31 1997-05-09 Janssen Pharmaceutica N.V. Farnesyl transferase inhibiting 2-quinolone derivatives
WO1997021701A1 (en) 1995-12-08 1997-06-19 Janssen Pharmaceutica N.V. Farnesyl protein transferase inhibiting (imidazol-5-yl)methyl-2-quinolinone derivatives
WO1998040383A1 (en) 1997-03-10 1998-09-17 Janssen Pharmaceutica N.V. Farnesyl transferase inhibiting 1,8-annelated quinolinone derivatives substituted with n- or c-linked imidazoles
WO1998049157A1 (en) 1997-04-25 1998-11-05 Janssen Pharmaceutica N.V. Farnesyltransferase inhibiting quinazolinones
WO1998055124A1 (en) 1997-06-02 1998-12-10 Janssen Pharmaceutica N.V. (imidazol-5-yl)methyl-2-quinolinone derivatives as inhibitors of smooth muscle cell proliferation
WO2000001386A1 (en) 1998-07-06 2000-01-13 Janssen Pharmaceutica N.V. Farnesyl protein transferase inhibitors for treating arthropathies
WO2000001411A1 (en) 1998-07-06 2000-01-13 Janssen Pharmaceutica N.V. Farnesyl protein transferase inhibitors with in vivo radiosensitizing properties
WO2000012499A1 (en) 1998-08-27 2000-03-09 Pfizer Products Inc. Alkynyl-substituted quinolin-2-one derivatives useful as anticancer agents
WO2000012498A1 (en) 1998-08-27 2000-03-09 Pfizer Products Inc. Quinolin-2-one derivatives useful as anticancer agents
WO2000039082A2 (en) 1998-12-23 2000-07-06 Janssen Pharmaceutica N.V. 1,2-annelated quinoline derivatives
WO2000047574A1 (en) 1999-02-11 2000-08-17 Pfizer Products Inc. Heteroaryl-substituted quinolin-2-one derivatives useful as anticancer agents
WO2001053289A1 (en) 2000-01-21 2001-07-26 Pfizer Products Inc. Anticancer compound and enantiomer separation method useful for synthesizing said compound

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
Kohl et al., "Selective Inhibition of ras-Dependent Transformation by a Farnesyltransferase Inhibitor," Science, 1993, pp. 1934-1937, vol. 260, No. 5116.
PCT International Search Report for PCT Appln. No. PCT/EP01/13317, mailed Feb. 5, 2002 which relates to this corresponding U.S. Application, filed herewith.
Rak et al., " Mutant ras Oncogenes Upregulate VEGF/VPF Expression: Implications for Induction and Inhibition of Tumor Angiogenesis," Cancer Research, 1995, pp. 4575-4580, vol. 55, No. 20.

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8232402B2 (en) 2008-03-12 2012-07-31 Link Medicine Corporation Quinolinone farnesyl transferase inhibitors for the treatment of synucleinopathies and other indications
US8343996B2 (en) 2008-11-13 2013-01-01 Astrazeneca Ab Azaquinolinone derivatives and uses thereof

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